Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. The results of our studies of adenosine receptors indicated that A2a receptors on the T cell surface may signal to block both thymocyte differentiation and effector functions of surviving mature T cells in conditions that lead to accumulation of extracellular adenosine. Our recent and ongoing experiments are designed to test the hypothesis whether the immunopathological effects of increased concentrations of adenosine in conditions of ADA deficiency can be at least partially explained by extracellular adenosine- triggered signaling. We demonstrated that in conditions of ADA deficiency, extracellular adenosine antagonizes TCR-triggered signaling and blocks the upregulation both of activation markers and of early activation events in thymocytes. In conditions of ADA deficiency, long-term (up to 4 days) survival of TCR-triggered thymocytes in vitro was accomplished by blocking the adenosine transporter-mediated accumulation of toxic intracellular adenosine. However, the surviving thymocytes had nonactivated phenotype because of extAdo-mediated, TCR-antagonizing signaling. Thus, the experimental data are consistent with the model where the intracellular toxicity of adenosine is mostly responsible for lymphocyte depletion, whereas extracellular adenosine interferes with normal differentiation and functioning of those 20-30% of T cells which do survive in conditions of ADA deficiency. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine (extAdo)-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. In addition, a proven role of extracellular adenosine-mediated signaling in mechanisms of ADA SCID will point to adenosine receptors as novel immunopharmacological target in treatment of this disease.